PROJECT SUMMARY/ABSTRACT This proposal was crafted to fast-track an improved understanding of the initiation and development of osteoarthritis (OA). Specifically, this work is designed to tease out the inflammatory and biomechanical contributions linking the infrapatellar fat pad (IFP) to knee degeneration. The central premise of this proposal is that early removal of the IFP beneficially alters the pathogenesis of primary OA in individuals susceptible to disease. In support of this theory, we have striking data in a rodent model that surgical removal of the IFP coincident with the onset of OA significantly decreased the short-term (4 month) progression of disease in the treated knee. We then demonstrated that this improvement may be related to the formation of a thick band of fibrous connective tissue (FCT) in the space previously occupied by the IFP. We postulate that there are two related, but potentially distinct, explanations for our findings: (1) removal of the IFP abrogated a critical source of detrimental inflammatory mediators not supplied by the replacement FCT; and/or (2) the development of the FCT in place of a comparatively lax IFP provided enhanced joint stability not present in its native state. To test our conjectures, experiments (as per our preliminary studies) will be performed in a translational guinea pig model that predictably develops primary OA with pathology identical to humans. The objective of the current project is to determine the benefits of the FCT versus IFP in minimizing/reducing knee OA. Our long-term goal is to identify explicit contributions of the IFP to OA so that interventional strategies can be strategized for prevention and/or treatment. Two Subaims are proposed: (1) to correlate the presence and severity of OA to the temporal expression and tissue distribution of inflammatory mediators in the IFP versus the FCT; and (2) to assess the contribution of the FCT versus the IFP on joint tissue biomechanical properties and joint biomechanics. Subaim 1 will use a combination of structural (histology and microcomputed tomography) and molecular (transcript and protein expression) outcomes to characterize OA and correlate it to catabolic cytokines/chemokines and adipokines. Subaim 2 will utilize cranial drawer tests, material property tests, and computer-aided gait analysis to determine tissue behavior and joint kinematics. This work is significant because it will make strides towards providing convincing evidence that the resident IFP is a contributor to joint deterioration, thus filling a void in the current understanding of OA pathogenesis. The proposed research is innovative because it will: (a) support early removal of the IFP in specific patients with an identified predisposition for OA; (b) elucidate properties of the IFP, which have been minimally documented in any species; and (c) discover changes in functional movement and symptom modification related to IFP removal that would not be highlighted by focusing on molecular or structural data, alone. Collectively, we expect to delineate the value of the FCT compared to the IFP, identify causative factors contributing to knee OA, and pinpoint endogenous cellular/tissue pathways for therapeutic exploitation.